Early retinal and cerebral deficits in a high fat diet + low dose STZ rat model of Type II diabetes

Abstract

Purpose : The high fat diet (HFD) + low dose STZ model was reported as a new model of Type II diabetes by Reed et al., 2000. In this model, rats are fed a high fat diet (40% kcal fat for 4 weeks), causing insulin resistance by 2 weeks. Rats are then given a single low dose of STZ (30 mg/kg vs. the 100 mg/kg used to create Type I diabetic rats), resulting in elevated blood glucose (>160 mg/dL compared with >250 mg/dL in the STZ model of Type I diabetes). Here, we examined early changes in retinal, cerebral, and metabolic function in this Type II diabetic model for 8 weeks.

Methods : Adult male Long Evans rats were assigned to one of the following groups: HFD+STZ (n = 6), HFD only (n = 5), and control rats (n = 4) that received normal rat chow. Visual function using optomotor response (OMR) was assessed every two weeks beginning just prior to HFD. Retinal function using electroretinogram oscillatory potentials (OPs) and cognitive function using Y-maze were assessed every four weeks. A panel of metabolic assessments, including measures of weight, fed and fasted blood glucose, insulin and glucose tolerance, and ELISA for blood insulin levels were also performed.

Results : Using our panel of metabolic assessments, we were able to determine which HFD+STZ rats exhibit a Type II phenotype (moderately high blood glucose levels and impaired glucose tolerance with insulin levels and weight gain close to control levels). In addition to metabolic changes, HFD+STZ rats showed deficits in OMR at 4 weeks post-STZ (9% reduction in spatial frequency) and delays in dim flash OP implicit times (12% delay) at 8 weeks. HFD only rats also showed OMR (5% reduction) and OP deficits (9% delay), but not to the same degree as HFD+STZ rats. Y-maze deficits were not observed in HFD+STZ rats by 8 weeks but may appear later in this model.

Conclusions : HFD+STZ rats exhibit a moderate diabetic state, while still showing retinal deficits typical of diabetes. This model may be more similar to Type II diabetes in patients. An observable retinal deficit at the 4-week time point matches our data in Type I (high dose STZ) and Type II (Goto-Kakizaki) models, indicating that 4 weeks of hyperglycemia induces retinal dysfunction regardless of the cause.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.